1. Field of the Invention
The present invention refers to the use of a p21-activated kinase (PAK) inhibitor for the treatment of a joint disease such as osteoarthritis or rheumatoid arthritis or for the treatment of a joint pain and the use of PAK as a target protein for the discovery of a PAK inhibitor as a medicament for the treatment of a joint disease.
2. Background of the Invention
Osteoarthritis is the most common disabling condition of man in the western world. Due to the aging of the population we have to face an ever-increasing population of patients, whose quality of life is severely affected. In addition, the disease carries a tremendous socioeconomic burden with high direct and indirect costs. The current treatment modalities concentrate on the management of the pain associated with osteoarthritis, but we are still completely lacking any pharmacological treatment modalities able to slow, stop or even reverse the course of the disease.
Osteoarthritis can be viewed as the clinical and pathological outcome of a range of disorders that results in structural and functional failure of synovial joints. Osteoarthritis occurs when the dynamic equilibrium between the breakdown and repair of joint tissues is overwhelmed. Structural failure of articular cartilage can result from abnormal mechanical strains injuring healthy cartilage, as well as from failure of pathologically impaired cartilage degenerating under the influence of physiological mechanical strains. Morphological changes observed in osteoarthritis include cartilage erosion as well as a variable degree of synovial inflammation. These changes are attributed to a complex network of biochemical factors, including proteolytic enzymes, that lead to a breakdown of the cartilage macromolecules. Cytokines such as IL-1 and TNFα which are produced by activated synoviocytes, mononuclear cells or by articular cartilage itself, significantly upregulate metalloproteinases (MMP) and cytokine gene expression, and blunt compensatory synthesis pathways. For example, activation of the AP1-transcription factor complex by IL-1 and/or TNFα through signal transmission via MAPK (mitogene activated protein kinase)-pathways plays an important role for the regulation of expression of marker genes that are relevant for osteoarthritis.
A further biochemical factor involved in cartilage catabolism and genesis of inflammatory pain is PGE2 (prostaglandin E2). PGE2, an eicosanoid synthesized by cycloxygenase (COX)-1 and -2, is involved in IL-1-mediated proteoglycan degradation, and administration of PGE2 into conscious rats or mice induces hyperalgesia. Endogenous expression of IL-1 leads to induction of COX-2 in the human osteoarthritis joint.
Consequently, osteoarthritis is characterized by a slow progressive degeneration of articular cartilage. The exact etiology of osteoarthritis is not yet known, but the degradation of cartilage matrix components is generally agreed to be due to an increased synthesis and activation of extracellular proteinases, mainly matrix metalloproteinases, and cytokines that amplify degenerative processes. Novel approaches to treat osteoarthritis are required, and progress in understanding the biology of cartilage disorders has led to the use of genes whose products stimulate cartilage repair or inhibit breakdown of the cartilaginous matrix. Several studies illustrate e.g. the potential importance of modulating IL-1 activity as a means to reduce the progression of the structural changes in osteoarthritis.
Therefore, an object of the present invention is to find new therapeutic ways for the avoidance or reduction of the effects of the cartilage harming factors.